The strategic use of memory is fundamental to the execution of goal-directed behavior and is hypothesized to be jointly supported by the prefrontal cortex (PFC) and medial temporal lobes (MTL); however evidence for a modulatory influence of PFC on MTL is still primarily indirect, as is the anatomical basis for these interactions in humans. The objective of the research in this proposal is to better characterize the pathways by which PFC and MTL interact during controlled memory processing through the application of effective connectivity analysis of functional magnetic resonance imaging (fMRI) data, guided by DTI tractography. Core data provided by the proposed research can serve as the basis for addressing fundamental mechanistic questions about the cognitive control of memory. In two fMRI experiments, we will systematically characterize the relevant pathways and dynamics between PFC and MTL under varying conditions of controlled retrieval - retrieval facilitated by top-down modulation of ongoing cue-driven memory retrieval. Controlled retrieval processing is recruited when automatic memory retrieval mechanisms fail to recover task- relevant information. As such, they are critical for the execution and planning of flexible, goal-directed behavior. Basic knowledge gained about cognitive control and memory is applicable to a number of clinical applications. Dementia is a pervasive symptom of neurological disease and a feature of many prevalent neuropsychological disorders such as ischemic vascular dementia and Alzheimer's and Parkinson's Diseases and the memory deficits that accompany healthy aging and development. As such, the proposed research could inform both diagnostic guidelines and the development of clinical treatments for patients afflicted with memory and executive dysfunction. The present proposal presents a necessary first step toward this broader research program. In three aims, we will: 1) identify regions within PFC and MTL activated during controlled retrieval using fMRI, 2) assess whether foci associated with controlled retrieval are material specific (preferentially process conceptual or visuospatial memoranda), and 3) characterize the functional-anatomic pathways by which PFC and MTL interact using diffusion tensor imaging (DTI) tractography and effective connectivity measures. PUBLIC HEALTH RELEVANCE: The proposed project seeks to characterize the functional pathways by which the prefrontal cortex and the medial temporal lobes interact during the cognitive control of memory. Basic knowledge gained about cognitive control and memory is applicable to a number of clinical applications as memory impairments are a pervasive symptom of neurological disease and a feature of prevalent neuropsychological disorders such as ischemic vascular dementia, Alzheimer's and Parkinson's Diseases, and are also associated with healthy aging and development. As such, the proposed research could inform both diagnostic guidelines and the development of clinical treatments for patients afflicted with impairments of memory and cognitive function.